Malignancies of B lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal B cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. The purpose of our studies was to determine if these mechanisms also contribute to mouse B cell lineage neoplasms, and to understand what they tell us about normal B cell biology. A high proportion of transgenic mice expressing the oncogene, TCL1, develop B cell lymphomas. We found that the environment in which these B cells mature was critical for tumorigenesis as mice that cannot generate germinal centers (GC) did not develop lymphomas. This showed that interactons of potential tumor cells with the GC microenvironment were critical to tumor develoment. Although it is known that most B cell lymphomas of adult humans develop in GC, the environmental stimuli leading to tumor development are not known. This mouse model system may provide opportunities to dissect those mechanisms. We also found that inactivation of TSGs contributed to TCL1-induced disease. In many cancers, TSG inactivation is caused by deletion of the gene or inactivating mutations of the DNA. We found that TSG inactivation in TCL1-induced tumors was caused by the epigenetic mechanism of DNA methylation resulting in inhibition of gene transcription. p27, another TSG, was found to be disabled in other lymphomas by enhanced degradation of the protein and sequestration away from its normal site of action in the nucleus. Sequestration was caused by binding of p27 in a novel cytoplasmic multi-protein complex not previously recognized in studies of human lymphomas or normal B cells. This finding may provide insight into a previously unrecognized pathway for controlling the rate of cell division in normal B cells as well as cancers. We also studied mice with inactivation of a gene, Artemis, involved in nonhomologous end joining, a critical DNA repair pathway for lymphocytes generating immune receptors for T cells and B cells. These studies showed that the mice provide a model for humans with radiation sensitive severe combined immunodeficiency that have an increased susceptibity to lymphomas. A deficiency in Artemis was found to accelerate the development of lymphmas and other cancers in mice lackng a copy of the TSG, p53. This indictes that Artemis is normally a TSG and that individuals deficient in Artemis may be at risk for both lymphoid and non-lymphoid cancers. Development of tumors was closely tied to the status of the TSG, p53. Since double stranded DNA breaks are a normal part of B and T cell development, understanding how they are normally repaired is critical to a deeper underastaing of lymphocyte biology. Mouse plasma cell tumors, called plasmacytomas (PCT), are usually considered to be neoplasms of fully mature plasma cells, to be due to chromosomal translocations that activate the Myc oncogene, and thus to be distinct from the human neoplasm of mature plasma cells, multiple myeloma. We identified a novel series of PCT that were not associated with Myc-activating translocations and that exhibted a maturational spectrum similar to that described for the progression of normal plasma cell develpment. This indicates that mouse PCT may be closer to multiple myeloma that was appreciated previously and could provide insights into this uniformly lethal disease. In addition, the relation of these tumors to normal developing plasma cells should provide important information on genes involved in the termnal stages of B cell development. Finally, we generated the first full characterization in mice of an uncommon neoplasm of mice and humans, megakaryocytic leukemia. We established phenotypic and molecular markers that clearly define this disorder and distinguish the disease from other hematopietic neoplasms.